The present application is the national stage under 35 U.S.C. 371 PCT/JP98/05172, filed Nov. 18, 1998.
This invention relates to conjugates which are useful in treating cancer and anticancer agents containing these conjugates as the active ingredient.
It is known that taxols such as docetaxel and paclitaxel inhibit cell proliferation based on the effects of promoting tubulin polymerization and stabilizing microtubules, thereby showing antitumor activity. Owing to these characteristics, taxols are expected to be useful as anticancer agents with a novel function mechanism. In particular, attempts have been made to clinically apply taxols to remedies for mammary cancer, ovarian cancer and nonsmall cell lung cancer (K. C. Nicolau, Nature, 367, 630 (1994); R. A. Holton, J. Am. Chem. Soc., 116, 1587 (1994); D. Masopaolo, A. Camerman, Y. Luo, G. D. Brayer and N. Camerman, Proc. Natl. Acad. Sci. USA, 92, 6920 (1995); Gan to Kagakuryhoho (Cancer and Chemotherapy) 21(5), 583 (1994)).
However, these compounds are poor in solubility and thus studies are in progress both in Japan and abroad to overcome this problem.
On the other hand, it is known that many tumor cells show overexpression of somatostatin receptor (Y. Yamada and S. Kiyono, Saibo Kogaku (Cell Technology), 12(9), 665 (1993); S. Kiyono and Y. Yamada, Naibunpitsugaku no Shinpo (Advances in Endocrinology), 10, 41 (1992)). It is also known that somatostatin derivatives such as octreotide show antitumor activity via the activity of inhibiting tyrosine kinase. In particular, Keri et al. recently reported a tumor cell-specific derivative TT232 (Gy. Keri, et al., Biochem. Biophys. Res. Comm., 191, 681(1993); Gy. Keri, et al., Peptide Research, 6, 281(1993); Gy. Keri, et al., (1993), Peptide Chemistry 1992, ed. N. Yanaihara (Leiden:ESCOM Science Publishers B.V.) pp. 334-336; Gy. Keri, et al., Proc. Natl. Acad. Sci. USA, 93, 12513 (1996)).
Moreover, bombesin-like peptides (GRP; gastrin releasing peptide, NM-C; neuromedin C) have been identified as autocrine growth factors of small cell lung cancer (SCLC) and it is known that receptors of these peptides are overexpressed on SCLC. Accordingly, it is expected that efficacious bombesin antagonists might be useful as anticancer agents specific to SCLC (F. Cuttina, Nature, 316, 823 (1985); D. H. Coy, J. Biol. Chem., 264, 14691 (1989); L. H. Wang, Biochemistry, 29, 616 (1990); D. H. Coy, Eur. J. Pharmacol., 190, 31 (1990)). The present inventors synthesized EABI [(E)-alkene-bombesin isostere] which contains an (E)-alkene type dipeptide lsostere (N. Fujii, Tetrahedron Lett., 32, 4969 (1991); N. Fujii, J. Chem. Soc., Perkin I, 1995, 1359) and clarified that this substance shows a potent antagonism in the amylase secretion system (M. Wada, Pancreas, 10, 301 (1995); N. Fujii, Peptides 1994, ed. H. L. S. Maia, Escom Science Publishers B.V. (1995), pp. 77-78; K. Fujimoto, Life Sciences, 60, 29 (1997)). In these days, it has been a practice to use cisplatin, carboplatin, etc. as the first-line drugs for SCLC. However, these drugs still suffer from some problems including side effects and the expression of tolerance thereto.
Therefore, it has been further required to develop drugs which are free from the problems encountering in the conventional anticancer agents, for example, short blood half time of peptide antitumor substances and poor solubility of highly efficacious anticancer agents such as paclitaxel derivatives.
An object of the present invention is to provide drugs with antitumor activity which are useful as remedies for cancer such as digestive system cancer, mammary cancer, ovarian cancer, lung cancer, etc., more particularly, anticancer agents comprising conjugates wherein a peptide ligand capable of binding specifically to a receptor expressed specifically in tumor cells is covalently bonded to a paclitaxel derivative via a linker.
As a result of intensive studies to solve the above-described problems, we found that the above problem can be solved by using conjugates and that the conjugates exhibit excellent effects as anticancer agents wherein one or more compounds with antitumor activity are chemically bonded to a peptide or a pseudopeptide having an affinity for a receptor expressed on tumor cells, thereby completing the present invention.
Accordingly, the present invention provides a conjugate wherein one or more compounds with antitumor activity are chemically bonded to a peptide or a pseudopeptide having an affinity for a receptor expressed on tumor cells.
The present invention further provides a compound represented by the following general formula (1) or potential tautomers, stereoisomers or optical isomers thereof:
Xxe2x80x94Lxe2x80x94Y
(wherein X represents paclitaxel or its derivative; L represents a linker having (a) functional group(s); and Y represents 
(wherein A1 represents a lysine residue, a citrulline residue, an arginine residue or an ornithine residue; and the amino and carboxyl groups bonded to the xcex1-carbon atom are each bonded to form an amide); or 
(wherein Z1 represents C(xe2x95x90O)NH or (E)CHxe2x95x90CH; Z2 represents C(xe2x95x90O)NH or (E)CHxe2x95x90CH; R1 represents H or a methyl group; R2 represents an isobutyl group or an isopropyl group; R3 represents H, an isobutyl group or a benzyl group; and R4 represents H or an isobutyl group); and * represents a bond to L.
The present invention further provides a compound represented by the following general formula (1) or potential tautomers, stereoisomers or optical isomers thereof:
Xxe2x80x94Lxe2x80x94Y
(wherein X represents paclitaxel or its derivative; L represents a linker having (a) functional group(s); and Y represents 
The present invention further provides a compound represented by the following general formula (1) or potential tautomers, stereoisomers or optical isomers thereof:
Xxe2x80x94Lxe2x80x94Y
(wherein X represents paclitaxel or its derivative; L represents a linker having (a) functional group(s); and Y represents 
Moreover, the present invention further provides compositions with antitumor activity and anticancer agents which contain the compounds represented by the above general formula (1) or potential tautomers, stereoisomers or optical isomers thereof.